MUMS Research - MRLs and Tolerances

Dr. Ronald Baynes
  

DR. BAYNES:  Let me thank the organizers, Art and Alistair and many others who invited me to come and give this controversial, if you like, talk or discussion about MRLs and tolerances.  I hope I can set the playing field for
Dr. Kornelia Greein who can go into more details on how this applies to MUMS.  What I thought, the function of me being here was to go over some of the rules for establishing MRL.    (Adjusting microphone.)
  
I hope at the end of the day I can convince you that there is a standard way you can go about deriving these MRLs, tolerances, here in the United States and internationally which are health-based derived safe levels. 
  (Slide.)
  
One of the first things I want to reiterate is that doing residues can be a risk to pubic health.  I want to talk about AMDUCA.  If it wasn’t for AMDUCA the Food Animal Residue Avoidance Databank would not exist.  I would like to talk about the pharmacological concepts that we use in deriving extended withdrawal time intervals.  This is the function of FARAD, I also want to ask the question why do we need to establish these safe levels. How do various agencies in the US -- predominantly the US is my focus -- and internationally establish these levels.  Then I want to --   (Laughter.)
  
DR. WEBB:  Start again.
  
DR. BAYNES:  Then I want to propose a transparent method, and transparent is a buzz word that we really like to use a lot nowadays, especially in the arena of harmonization of standards across the board and tolerances and MRLs.  We have come up with a term called a PAR thanks to Dr. Craigmill and Dr. Tomas Martin of Illinois now, and Dr. Jim Revere and myself.  We are saying basically a PAR is similar to a tolerance or an MRL, but it is transparent.
  
Let me first of all before I get to the slides say that what is driving these two things.  Based on AMDUCA, we are required to come up with an extra-label, and extended extra-label withdrawal time.  In order to do this, we need to have tolerance.  If there is no tolerance or there is no MRL, we need to come up with one.  This is where the PAR fits in here.  Okay?  Once we have that line, that horizontal line, then we can pretty much go to the kinetic data and begin to come up with an estimation of an extended withdrawal time for extra-label drug use.  This of course applies to MUMS.    (Slide.)
  
Can people really get sick from drug residues?  Yes.  A classic example is what happened in Spain and France over 10, 12 years ago where people were exposed to livers which were tainted with clenbuterol.  We also have here in the United States six of 38 animals tested at a state fair in 1995 with clenbuterol, and the FDA is well aware of this.  We have individuals who are compounding and smuggling several of these illegal products, or these prohibited products.
  (Slide.)
  
What are these drugs?  Many times they can be over-the-counter or prescription drugs, but I put this up here to emphasize the fact that over-the-counter antibiotic drugs can lead to antibiotic residues.  These are probably the majority of drugs sold in the United States.  So many times if you use these drugs not according to the label, you can result in antibiotic residues. 
  (Slide.)
  
The next category of drugs I want to talk about are the prohibited drugs, and this list is growing since AMDUCA  came into being in 1994.  I heard someone talk about chloramphenicol yesterday being used.  Chloramphenicol is nasty substance.  It causes aplastic anemia.  Therefore it has been pulled for use in animals.  This list I have here is for the dairy.  I normally supply  this list to dairy practitioners, but this can be applied to other species.  Clenbuterol is there; colloidal silver; DES; DMSO; dipyrone, no longer in many veterinary practices; enrofloxacin for obvious reasons has some very strict, strict label uses.   A strict label uses includes the fact that, it cannot be used dairy; and in the last three or four years nitrofurazone; and of course nitroimidazoles because of the mutogenic concerns with these class of drugs.
  (Slide.)
  
Another group of chemicals, moving away from drugs now, are the pesticides.  We tend to ignore these, and this is where our PAR approach can be applied across many species irrespective of whether a drug or a pesticide.  Treat it as a chemical.  In another words, you are not tied down, you know, with extrapolations jut to drugs.  So we can have accidental exposure, terrorist exposure, you name it.  Some of these nasty substances, whether it is dioxin in Europe back in 1999.  In this case, we were able to come up with a recommendation to the folks in Brussels for dioxin exposure.  So these are the kinds of chemicals that we need to pay attention, just not drugs alone.
  (Slide.)
  
AMDUCA, the Animal Medical Drug Use Clarification Act, 1994 came into existence after a lot of hard work.  This slide says that extra-label use of drugs has been legalized and FDA CVM in the United States has published regulations for extra-label drug use.  FARAD is a major source of extra-label drug use information.  This legislation as far as I am aware is not in existence in Canada and other countries, but other countries for the last couple of years have developed a FARAD kind of program, especially in Canada.  They are also recognizing the need to generate a database from which we can make extrapolations, and this is through the mechanism of Canadian G-FARAD.
    (Slide.)
  
What are these guidelines on AMDUCA?  What are these guidelines?  These are very strict guidelines.  You must have a valid veterinarian-client-patient relationship.  Use currently marketed drug for the disease, or recommended does is ineffective.  For example, a veterinarian cannot say, "I want to use phenylbutasone because it is cheap instead of  banamine.  Banamine has been out there on the markets approved for cattle.   This product is obviously more expensive than phenylbutasone ---, but the law does not allow or rather the law says you need to use the currently marketed  product.  Some of you may be aware of a concern and the controversy around fenylbutezone.  We won’t go through that.  We don’t have time for that this morning. 
  
You must have records and other measures to identify the treated animals.  You must have some indication.  Then you must significantly extend the withdrawal period.  Significantly extend the withdrawal period so there are no illegal residues.  This information is not on the bottle.  It doesn’t say 2X dose two days, 3X dose four days.  It is not there on the bottle.  So where do you go from there?  This is why FARAD is in existence, to provide this information. 
  (Slide.)
  
This is one of three kinetic slides, so bear with me.  We can use a drug, give it by some route (eg), by IV administration.  You get an absorption phase going from left to right.  Then you get an elimination phase.  What we do in FARAD is that we use the residue elimination phase, to come up with some explanation of the half life.  We extrapolate that back to the tolerance or the MRL.  I will talk a little bit later why you can’t use the MRL if it is in the United States.  We use a tolerance or a PAR, which is similar to a tolerance, and where those lines cross, that is our withdrawal time.  That is of course is an over simplification.
  (Slide.)
  
What if you give a larger dose?  If you give a dose and it results in a concentration of 10 parts per million --.  Then you double the dose, and we are assuming linear kinetics.  The dose, the concentration in the tissue is obviously doubled to 20 parts per million.  You can see again provided the elimination is linear, the rate constants should be the same and the half life should be the same as seen by the slope.  What if you have a change in clearance and a change in drug distribution?  Protein binding, disease processes can change distribution resulting in differences in protein binding.  Physiological changes in the animal can result in clearance, changes in clearance.  So as a result of that the slope will change.  You get the less steep slope.  So the half life will change, and therefore because of that slope moving to the right you will get an intercept now to the right, which crosses the tolerance level.  So obviously in a diseased animal or the change in physiology, you expect to get an extended withdrawal time period.  Somebody alluded to that I believe yesterday, about concerns of diseased animals; withdrawal times are going to change.
  (Slide.)
  
What we are trying to do here at FARAD is to model these effects.  We are not to the physiological and disease state yet.  What we are trying to do many times is model the simplest scenarios.  That is looking at dose effect.  So all that preamble gets to really what should be my first slide, how is the tolerance derived for this example of oxytetracycline.  Where would you place the tolerance line?  That is the question I ask.  Where do you place the tolerance line for milk data for goats and for cattle?  For cattle, yes, we know.  In the United States that tolerance line should be 0.3.  In the United Kingdom and Europe it is 0.1. 
  (Slide.)

Let’s step backward and look at the process that FDA CVM uses.  We first of all have to recognize that when a study is conducted we are normally going to use data from a series of animals, sometimes 25 animals, five animals for each time point.  We are going to come up with a average, which is the central line through there, and around that we have of course the confidence interval.  So we are going to be looking for the slowest peaking animal, with a conference interval around it.  Now where that line crosses the tolerance or the MRL, that is going to be the withdrawal time. 
  
The examples I have up here are for tolerance one or MRL one, tolerance two or MRL two, is to show you by shifting those lines around, shifting those safe levels around, you can significantly affect the withdrawal time.  Okay?  The withdrawal time will be increased or decreased depending upon the level.  So this slide is showing you a number of things that are important at the regulatory level. 
  (Slide.)
  
This is our strategy.  For the last couple of years we have been asking questions ---, at CVM, at JECFA.  How do you guys do this?  Give us an example.  Please make it transparent so we can get on with the job of doing extra-label withdrawal time based on AMDUCA.  It has been hard.  It has been very difficult.  So what we did was come up with our own system.  This is the PAR.  This system is going to be a mirror image of what is going on in the United States.  The aim is to make it transparent so we can do the extrapolations. 
  
The reason why we want to do this is if you don’t have a US tolerance or a safe concentration, we need to go back to the toxicology data.  It should be available to all of us because it is a drug submission package, and look at the NOEL and ADI or look at the safety factors.  All those are important in coming in with the acceptable daily intake (ADI).  Well, we can spend another hour talking about NOELs, the problems with NOELs.  Why don’t we use benchmark dose?  Why aren’t PBPK methods being used in deriving a better reference dose?
  (Slide.)
  
Safety factors are another big issue.  All the safety factors, (all the tens and the thousands) are used to drive ADI.  So we are primarily using the same data package to come up with these parts.  Some folks say, "Well, why don’t you use the MRLs?"  One of the public comments yesterday was about that.  Why don’t we just use MRLs so that  minor species, equals major species.  No, that is not going to work here in the United States or in Europe.  In some cases foreign MRLs always equals to US tolerances.  The drug we are now working on, sulfamethazine has a MRL of 0.1 PPM, and for the last five years it wasn’t explained to me why all tissues have a tolerance of 0.1 parts per million.  Anyway, generally they are not always equal.  So one can not always extrapolate MRLs for all purposes.  Foreign methods differ from US methods because of partitioning of the ADI.  Once you derive that ADI how that is partitioned varies from country to country.  Gut flora are considered.  The NOELs are differently as I said.  The MRL determinations are not always strictly health based because of some of the changes sometimes occur at the end of the process.  Even though NOELs may be the same, they are not always strictly health based.  There is always some fudge factor thrown in there at the end, and I can also say that for the tolerances as well.  I don’t want to pick on the MRLs alone.
  (Slide.)
  
I just grabbed a few drugs, threw them together.  I should get a straight line right?  Should be a nice straight line if we are going to harmonize MRLs and tolerances.  These are JECFA MRLs on the left, US tolerance on the right.  I believe this is for the liver.  The liver is the marker target tissue, and we are looking at albendazole, ceftiofur, there is only one that is sort of compliant, neomycin.  You see tetracycline there to the far right.  We --- see problems here with tetracycline with the tolerance being six times that of JECFA’s MRL.  So you see the problems why we can’t use MRLs here for our estimation. 
  (Slide.)
  
So what we are saying is the PAR is similar to the US FDA definition of a safe concentration.  We were looking at total residues.  Again, a safe concentration is equal to the ADI times the body weight divided by the food consumption values.  Again, another variable, and a variable which has a wide distribution within itself because food consumption varies across the populations, even within a population.  An ADI now is the NOEL divided by the safe factor.  The NOEL is the greatest amount of drug found, or toxicant or chemical, found to cause no observable adverse effect in the test animal.
  (Slide.)
  
The NOEL is now divided by these safety factors.  As I said, these safety factors can be 100, can be 200, 300, 2,000, 1,000.  These are some of the reasons why we have these numbers here.  The 100 comes from 10 times 10, where the 10 comes, the 10 is for interspecies, and other 10 for interspecies variability.  Then that 10 is also looking at pharmacokinetic differences, so we have these safe factors, which are fudge factors if you like, which are thrown in there to pretty much provide an estimate until we can have some idea of what that uncertainty is.  Where that uncertainty occures, we will use 10.  Okay?  It is a very conservative value in coming up with that NOEL.
  (Slide.)
  
Food consumption values, as I said, is another variable in this estimation of MRL and tolerances.  We assume based on these total basket dietary studies that have been done over the years that we consume 300 grams of muscle, 100 grams of liver, and so on.  We can assume we consume 1.5 liters of milk per day for 70 years.  Okay?  These are the estimations.  These are some of the estimations we use.  We assume --- more milk and more muscle than other organ tissues, and we really do not eat a full portion of meat product, and this of course pertains to MUMS.  Individuals do not always eat a full portion of meat product from another species.  A big assumption there as well.
  (Slide.)
  
So where are we now?  Do we go with the ADI?  This then gets to a situation where I am showing you where all these variables can impact that ADI, the NOELs, the safe factors and uncertainties associated with it.  We are going to take that ADI, and we need to move on now to derive that safe level, that tolerance, that PAR, that MRL, whatever you want to call it.  How do we get there?
  (Slide.)
  
The next step, partition this ADI.  How we partition this is a matter of deep controversy again.  We can spend a week workshop talking about that.  Okay?  We won’t.  What I found in our research is that FDA, the US FDA, CVM, will follow a procedure which sort of mirrors procedure A where they have taken 50 percent of that ADI.  Right, for the target tissue, muscle, and then reserved 50 percent for milk.  Sometimes they reserve 90 percent for milk.  It varies.  Again, you see the variability of procedure A. 
  
Procedure B.  Just like the previous speaker, I was trying to understand what is going on at the regulatory level so we can better estimate a safe level for primary purposes.  The primary purpose, to get an extended withdrawal time for extra-label drug uses.  This again applies to MUMS.
  
Once we decide how we are going to partition it, we divide the ADI by food consumption value, and I think all countries agree with this.  Okay, 0.3 kilograms of muscle and so forth.  We then come up with a safe concentration for total residues.  That is what the safe concentration refers to.  Then we obtain residue depletion data and begin looking to see if there is metabolism, and if there is metabolism then that metabolite is the marker residue.  Otherwise a paired compound is what we want to monitor. 
  (Slide.)
  
This profile here is just a simplification of what  goes on here.  Once we have the total residues, we can pretty much derive a safe concentration or a PAR, okay, for that tissue.  If the marker residue as I said is a metabolite, we can come up with a tolerance of what we call a provisional acceptable tissue -- sorry, provisional acceptable tolerance or PAT.  We like kind of acronyms at FARAD.  But it works for us because we can estimate again a safe withdrawal time provided we have this horizontal line.  You want a safe line for which to estimate a withdrawal time.
  (Slide.)
  
So I said there are three procedures that I have been able to derive or been able to glean from my observations from all the data that has been approved around the world, and the PARs A -- just summarizing.  PARs A, PARs B, PARs C, pretty much is how we are going to go about coming up with a safe level.  You can use either one or the other, depending on the situation.  To my example, I only have one example. 
  (Slide.)
  
Some of you may have heard this talk before.  I given three, four examples, and by the way this was published several years ago in Regulatory Pharmacology Toxicology.  I don’t have time to go through this entire slide, but what I want you to focus on is that of PARs A look at the values for PARs A which we were able to come up with.  They are similar to the US tolerances, current US tolerances in the United States.  The asterisk pertains to the old US tolerances.  We saw the mirror of JECFA’s MRLs, and you can see the total maximum daily intake at the bottom, TMDI, and you can see it pretty much exceeds the ADI to some extent, significantly if you use the US tolerance.  A matter of contention, an issue, we can debate that ad nauseam, but I won’t.
  (Slide.)
  
The answer to the original question is the US tolerance for tetracycline is 0.3 parts per million under current regulations of the CFR, and this is similar to the PARA procedure, but the EU MRL is 0.1 part per million.  So if the US uses a foreign approved MRL or withdrawal time, this means -- I have to tell the dairy producers here, “I’m sorry you have to throw away more milk.”  Primarily because you have to extend the withdrawal time.  So this is a scenario here.  These are some of the problems when you are trying to extrapolate across MRLs or using MRLs in the United States.
  (Slide.)
  
A summary of basically what I have just said is that there is little or no -- correlation, but really no correlation between US tolerances and foreign MRLs.  In the case of oxytetracycline and the tetracycline family there can be as much as 20 times -- (this is for liver), the EU MRL.  This can result in total maximum daily intakes for us humans based on the assumptions I said, 1.5 liters of milk consumed per day for 70 years and so on -- can result in a TMDI here --- ADI, acceptable daily intake which is based on the tox data.  PARs and PATs, which are the safe concentrations of tolerances, are comparable to US tolerances for tetracycline.  Safe concentrations were found here for ivermectin somewhat.
  
Dexamethasone is a classical one I like to talk about because dexamethasone is approved for use in the United States with no tolerance.  There is no tolerance set.  But under AMDUCA, why would you give dexamethasone to a dairy cow at a higher dose than approved?  If so, you have to come up with some kind of tolerance.  This is where FARAD fits in.  This is what we have been doing.  Okay?  Azaperone is another good example. 

Partitioning methods, by agencies are inconsistent and difficult to follow.  With tetracycline you notice a 40 percent allocation to tissues, 60 percent to milk, not the 50/50 as I said before.
  (Slide.)
  
These enforceable residue levels can be established on health-based principles, not politics -- or how you feel today.  PARs and PATs insures that the TMDI is less, can be less, total maximum daily intake or less than ADI.  These values may be used in the advent of accidental exposure to contaminants or any terrorist chemical attack on food supplies if you like, or as is primarily the function of FARAD in extra-label drug use.  Okay?  The estimated safe withdrawal interval.  These methods are transparent and hopefully would encourage harmonization.  Thank you.
  (Applause.)
  
DR. WEBB:  Our final speaker of this morning’s session is Dr. Kornelia Grein.  She says she is a qualified chemist and a pharmacist, so I guess druggists are in again.  She holds a PhD in chemistry from the Free University of Berlin, and she worked for a period of time as a pharmacist.  She then joined the dark side like all these other people did and she went to the German environmental agencies and was scientific administrator in risk assessment.  She was --- to the European commission in adoption and implementation of the EU legislation on existing chemicals.  She then went to EMEA as head of sector for Safety of Veterinary Medicines, and she is also a coordinator for regulatory authorities with the VICH.